Recently much progress has been made in the understanding of hair follicle (HF) biology. The HF is a dynamic structure whose multiple compartments undergo successive rounds of complex and highly synchronized architectural reorganization during the growth (anagen), regression (catagen) and resting (telogen) phases of the hair cycle. Mutations in the hairless (hr) gene, which cause alopecia in mice and other animals and atrichia with papular lesions (APL, OMIM 209500) in humans, result in cellular and morphologic changes in the structure of the HF that have been characterized, yet little is known about the regulation of hr expression or the molecular mechanisms disrupted by h r mutations. The striking similarity in pathologies of the hairless mouse and the Vitamin D Receptor (VDR) null-mutant mouse has led to the suggestion that Hr and VDR are functionally related in the hair cycle pathway. The recent cloning of the hr promoter has revealed the presence of a putative VDR response element in a relevant location within the promoter. Although mutational analysis has identified two different grups of genes that lead to hair phenotypes, those that result in defects in follicle morphogenesis and those that exhibit deficiencies in HF cycling, we report in our preliminary data a relationship between members from each group, hairless and Lefl. Our preliminary data demonstrate that h r promoter activity can be regulated by Lefl in a beta-catenin dependent manner. This proposal aims to demonstrate that hr expression is regulated by a functional VDREin its promoter. Additionally, ince we have discovered a molecular link between the anagen and catagen phases of the hair cycle, this proposal aims to define the genetic interactions between the Wnt pathway and hairless gene expression in order to understand the molecular basis of HF cycling.